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The development of vaccines against infectious diseases requires a different approach from that of therapeutics, because vaccines are inoculated into healthy individuals and have a preventive effect by activating the immunity of the inoculated human. In Japan, "The Guideline for Clinical Trials of Vaccines for the Prevention of Infectious Diseases" was published in 2010 before changes occurred in the vaccine development environment in Japan, such as the introductions of foreign vaccines and simultaneous global development. This study aimed to identify current challenges in vaccine development through a questionnaire-based survey of pharmaceutical companies in Japan and by comparing the domestic and international guidelines and surveying review reports of 35 vaccines approved in Japan between April 2010 and December 2020. Identified challenges included the requirement for protective efficacy trials, efficacy evaluation of combination vaccines, development of multiregional and foreign clinical trials, and immunization of older adults and immunocompromised patients. We propose that new vaccines against infectious diseases should be evaluated for the protective efficacy, preferably through multiregional clinical trials. Additionally, differences in the incidence of infectious diseases or in epidemic virus strains between regions may affect the trials, when multiregional clinical trials are conducted, but immunogenicity-based studies can be conducted if a correlation between protective efficacy and immunogenicity has been established. We suggest that licensed combination vaccines can be used as comparators when an antigen is added to a licensed combination vaccine. We also proposed that the efficacy of a vaccine in non-major subjects, such as older adults or immunocompromised patients could be evaluated by comparing immunogenicity in major subjects with the confirmed protective effects of the vaccine. It is expected that these revisions will lead to the rapid advancement of vaccine development, which should contribute to the improvement of public health.

Hydroxypropyl-β-cyclodextrin (HP-β-CyD), an oligosaccharide used as an excipient in pharmaceutical preparation, was recently reported to function as a vaccine adjuvant to co-administered antigens. In this study, we investigated the safety and immunogenicity of a seasonal influenza vaccine adjuvanted with HP-β-CyD (FluCyD-vac) in healthy adults compared with those of a standard seasonal influenza vaccine (Flu-vac).We conducted a single-blinded randomized phase 1 clinical trial study, and used two quadrivalent split seasonal influenza vaccines: FluCyD-vac containing 9 μg of HA/strain and 20% w/v of HP-β-CyD, and Flu-vac containing 15 μg of hemagglutinin (HA)/strain only. All participants were randomly assigned to receive a single dose of Flu/CyD-vac or Flu-vac at a ratio of 2:1. We assessed solicited and unsolicited adverse events (AEs) and immune responses using hemagglutination inhibition (HI) titers. In addition, we assessed T-cell function in peripheral blood mononuclear cells (PBMCs), after stimulation with HA vaccine strains, using flow cytometry.Among 36 healthy volunteers enrolled in the study (FluCyD-vac, n = 24; Flu-vac, n = 12), FluCyD-vac was well tolerated. Most of the solicited AEs were mild local skin reactions at the injection site. No serious AEs were reported in either group. HI titers 21 days after vaccination with FluCyD-vac were comparable with those of Flu-vac and sufficient to meet international criteria, despite reduced HA antigen doses. When PBMCs were stimulated with the four HA antigens in the vaccine, tumor necrosis factor (TNF)-α-producing CD4FluCyD-vac was well-tolerated and immunogenic, despite containing 40% less HA antigens than Flu-vac. This study showed that HP-β-CyD is a potentially safe, novel adjuvant for human influenza vaccine.UMIN000028530.

The efficacy and safety of vaccines for the prevention of infectious diseases are mostly evaluated based on the induction of an immune response against antigens, and do not necessarily depend on the dose administered. Therefore, there are some specific aspects that need to be considered in the development of vaccines and have been described in "The Guidelines for the non-clinical studies of vaccines for the prevention of infectious disease" in Japan. Recent changes in the vaccine development field, such as the introduction of vaccines developed overseas in Japan and vaccine development on a global scale have increased the need for revision of these guidelines. In this study, we identified the current challenges in the development of vaccines through comparison of Japanese and international guidelines. We conducted a questionnaire-based survey of pharmaceutical industries in Japan, and found issues related to non-clinical studies, such as the necessity of safety pharmacology studies and repeated-dose toxicity studies for each route of administration. We examined international guidelines on these issues as well as review reports by regulatory authorities, and determined that the results of repeated-dose toxicity studies can be used to decide whether safety pharmacology studies are required, and that studies to evaluate toxicity due to systemic effects may not be necessary for both intramuscular and subcutaneous administration. We propose revision of the guidelines for the non-clinical studies of vaccines in Japan taking international harmonizaion into account. We expected that the revised guidelines will promote smooth and rational vaccine development.

After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of the BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in the BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2.

Molecular dynamics simulations are used to examine the relationship between oxide ion conductivity and dopant content in systems of general formula Ba1−xSrxCo1−yFeyO2.5, where x and y are varied between 0 and 1, and all B-site cations are assumed to be in the + 3 state. Doping Ba-rich systems with iron initially causes a decrease in the ionic conductivity, which reaches a minimum around 50 at.% Fe. Above this concentration, the conductivity increases again to a maximum for y = 1. For Sr-rich systems (x = 1.0), the conductivity increases continuously as y is increased. Simulations using a mean field approximation for the short-range Co3+/Fe3+ interactions are also reported; comparison with the discrete ion model results shows that the parabolic variation in the ionic conductivity is due to a mixing effect caused by the random distribution of dopant ions in the perovskite structure. Calculation of coordination numbers for each cationic species shows that anion vacancies tend to be strongly associated with Co3+ ions, and that the strongest bonding occurs when y = 0.5. Doping with Sr2+ was found to increase the conductivity. These results show that compositional changes have a strong effect on the oxide ion conductivity when the concentration of oxygen vacancies is held constant.

A new straw-tube gas chamber which is made of seamless straw-tubes, instead of ordinary wound-type straw-tubes is developed. Seamless straw-tubes have various advantages over ordinary wound-type ones, in particular, in terms of mechanical strength and lesser wall thickness. Our seamless straw-tubes are fabricated to be resistive so that the hit positions along the straw axis can be read by cathode planes placed outside the straw-tube chambers, where the cathode strips run transverse to the straw axis. A beam test was carried out at KEK to study their performance. As a result of the beam test, the position resolution of the cathode strips of 220 μ m is achieved, and an anode position resolution of 112 μ m is also obtained.

Free energies of the hexagonal phase and perovskite phases of BaCo 1− y Fe y O 3− δ , a mixed ionic and electronic conductor, are calculated using first principles method. The calculated structure of a known phase is in good agreement with experiment. It is found that the hexagonal phase is most stable at low temperature. As temperature increases, a phase transition to tetragonal perovskite, in which the B site cation valence is reduced to 3+ by release of oxygen, takes place. Further increase of temperature results in the reduction of the perovskite phase, i.e., the valence of the B site cation is reduced to 2+. The temperature of the hexagonal to perovskite phase transition is lowered by mixing Co and Fe, in spite of the increased phonon scattering, due to localization of oxygen vacancies.

The porous catalytic layer of perovskites was coated on either surface or both surfaces of the dense membranes of LSCF perovskites with nearly 1-mm thickness, and the catalytic effects on the oxygen permeation flux under the air/He gradient were investigated. The observed catalytic effects were discussed mainly on the basis of the oxygen sorption–desorption capacity (OSDC) of membrane and catalyst materials. The coating on the anode side improved the oxygen flux in any combinations of the membrane and catalyst materials having different OSDC, and an increase in the anode surface area, where oxygen association reaction takes place, is primarily responsible for the enhancement by the anode coating. The effect of the cathode coating, on the other hand, depended significantly on the relative difference in OSDC of the membrane and catalyst materials: for example, the oxygen permeation flux was enhanced and reduced by coating with perovskites having larger and smaller OSDC, respectively. It has turned out that the cathode materials should have large OSDC. The behavior of membranes modified on both sides could be understood in terms of a simple sum of the cathodic and anodic effects.

We have examined by the liposome swelling technique the permeability properties of the modified LamB proteins isolated from mutants of Escherichia coli K12 with altered affinities toward starch and/or maltose (Ferenci, T., and Lee, K-S. (1982) J. Mol. Biol. 160, 431-444). The results revealed the following. A mutant strain exhibiting a markedly lowered affinity toward starch produced a LamB protein that has lost the ability to permeate longer maltodextrins. This protein retained a nonspecific pore for a wide variety of small sugars. A mutant strain with partially reduced affinity for starch produced a LamB protein which still permeated maltodextrins, maltose, and non-maltose sugars but had also gained an ability to permit the diffusion of sucrose and raffinose; in this strain sucrose and raffinose could now compete for the starch-binding site. A mutant with enhanced affinity for both maltose and starch produced a protein which exhibited elevated rates of diffusion for longer maltodextrins but still permeated other small sugars. Two other mutants with altered affinities showed relatively minor changes in the diffusion of maltose and non-maltose sugars. It could be concluded from these studies that the LamB proteins form pores allowing the diffusion of a wide variety of monosaccharides irrespective of the presence or the absence of affinity of a binding site for maltodextrins. However, the presence of a sugar-binding site is crucial in determining the rate of the diffusion of maltodextrins or other oligosaccharides.

Oligomers of a protein, porin, form permeability channels in the outer membrane of Escherichia coli B. A functional porin oligomer was identified and was purified to homogeneity by gel filtration in the presence of salts and sodium dodecyl sulfate. Molecular weights of purified porin oligomer and heat-dissociated monomer appeared to be 102,900 and 32,600, respectively, when determined by sedimentation equilibrium in the presence of sodium dodecyl sulfate. We concluded that the porin oligomer thus consists of three identical subunits. These data and results from other laboratories suggest porin trimers exist also in the outer membrane of intact cells, and participate in the formation of permeability channels. It was found that porin trimer bound less sodium dodecyl sulfate than the porin monomer.